Several types of self-hardening calcium phosphate compositions have been studied (Brown and Chow, A New Calcium Phosphate Water Setting Cement, pp. 352-379 in Brown, Cements Research Progress, American Ceramic Society, Ohio, 1986; Ginebra et al., Setting Reaction and Hardening of an Apatitic Calcium Phosphate Cement, J. Dent. Res. 76:905-912, 1997; Constantz et al., Histological, Chemical, and Crystallographic Analysis of Four Calcium Phosphate Cements in Different Rabbit Osseous Sites, J Biomed Mater. Res. [Appl. Biomater.] 43:451-461, 1998; Miyamoto et al., Histological and Compositional Evaluations of Three Types of Calcium Phosphate Cements When Implanted in Subcutaneous Tissue Immediately After Mixing, J. Biomed. Mater. Res. [Appl. Biomater.] 48:36-42, 1999; Lee et al., Alpha-BSM(R): A Biomimetic Bone Substitute and Drug Delivery Vehicle, Clin. Orthop Rel. Res. 367:396-405, 1999. Because of its chemical and crystallographic similarity to the carbonated apatitic calcium phosphate mineral found in human bones and teeth, hydroxyapatite has been one of the most often used restorative materials for the repair of human hard tissues
One of the calcium phosphate compositions, developed by Brown and Chow in 1986 and named calcium phosphate cement, or CPC, self-hardens to form hydroxyapatite as the primary product. The term “self-harden” refers to the paste being able to harden by itself. For example, the CPC paste can be placed into a bone cavity, and can self-harden after contact with an aqueous medium. CPC typically may be composed of particles of tetracalcium phosphate (TTCP: Ca4(PO4)2O) and dicalcium phosphate anhydrous (DCPA: CaHPO4) that react in an aqueous environment to form solid hydroxyapatite, Ishikawa et al., Reaction of Calcium Phosphate Cements with Different Amounts of Tetracalcium Phosphate and Dicalcium Phosphate Anhydrous, J. Biomed. Mater: Res. 46:504-510, 1999; Matsuya et al., Effects of Mixing Ratio and Ph on The Reaction Between Ca4[PO4]2O and CaHPO4, J. Mater. Sci.:Mater. in Med. 11:305-311, 2000; Takagi et al., Morphological and Phase Characterizations of Retrieved Calcium Phosphate Cement Implants, J. Biomed. Mater. Res. [Appl. Biomater.]58:36-41, 2001. Calcium phosphate compositions (such as CPC) are highly promising for a wide range of clinical uses due to their excellent biocompatibility, osteoconductivity and bone replacement capability. For example, CPC has been studied for use in the reconstruction of frontal sinus and augmentation of craniofacial skeletal defects (Shindo et al., Facial Skeletal Augmentation Using Hydroxyapatite Cement, Arch. Otolaryngol. Head Neck. Surg., 119:185-190, 1993), endodontics (Sugawara et al., In vitro Evaluation of the Sealing Ability of a Calcium Phosphate Cement When Used as a Root Canal Sealer-Filler, J. Endodont. 16:162-165, 1990), and root canal applications (Chohayeb et al., Evaluation of Calcium Phosphate as a Root Canal Sealer-Filler Material, J. Endodont. 13:384-387, 1987).
Most of the presently available calcium phosphate cements are mixed with an aqueous solution prior to use. Accordingly, the ability of the surgeon to properly mix the cement and then place the cement paste into a bone defect within the prescribed time prior to cement hardening is a crucial factor in achieving optimum results. The art thus has recognized the desirability of providing pre-mixed cement pastes that are stable as provided but that harden only after being introduced to the bone defect and positioned appropriately. Pre-mixed self-hardening cements may be formulated by combining glycerol, sodium phosphate, hydroxypropyl methyl cellulose and calcium phosphate cement powders, as described in Takagi et al., “Properties of premixed calcium phosphate cement pastes,” J. Biomed Mater Res. [Applied Biomater] 67B:689-696 (2003). The hydroxypropyl methyl cellulose and sodium phosphate used in such pastes are believed to improve paste cohesiveness and accelerate cement hardening, respectively. The hardening times of the forgoing cements are about 60 minutes, which is much longer then 5- to 30-minute setting time desired in many cases.
Organic acids, such as glycolic, citric, tartaric, malonic, malic, maleic, and so forth, may be used as setting accelerators instead of sodium phosphate. In such cases, the pre-mixed cements can harden in significantly shorter times (10 minutes to 35 minutes) (Chow et al., “Rapid-Hardening, Pre-mixed Calcium phosphate cement pastes,” Abs. No. 844, J. Dent. Res., Spec. Iss. A82 (2003)). The rapid hardening of these pre-mixed pastes is due to formation of carboxyl/calcium complexes, rather than the formulation of hydroxyapatite, which is the mechanism responsible for cement hardening in most conventional calcium phosphate cements. Despite the lack of hydroxyapatite formulation, several carboxylic acid/calcium phosphate cements had been reported to produce excellent bone defect repair results in vivo.
A third type of pre-mixed calcium phosphate cement has been reported (Carey et al., “Premixed Rapid-Setting Calcium Phosphate Composites for Bone Repair,” Biomaterials 24:5002-14 (2005)). The cement hardening in these pre-mixed cements results from formulation of a hard hydrogel produced by a reaction between chitosan, a water soluble polymer, and an alkaline compound such as tetracalcium phosphate or calcium hydroxide. After initial hardening, further reactions between calcium phosphate salts form hydroxyapatite as a major end product in the cement.
To provide stability, the heretofore described cements are formulated as non-aqueous pre-mixed materials. Cement hardening does not begin until these precursors are placed into a bone defect, whereupon water from surrounding tissues enters into the cement. These cements, while often possessing excellent physical properties, sometimes can be limited in utility. Cement hardening in the interior of the cement mass may be slow under some clinical bone grafting conditions, for instance, wherein the amount of water available from the tissues is limited, or wherein the interior of the cement is more than several millimeters away from the nearest graft-tissue interface. Additionally, such cements typically are required to be formulated to be able to react extremely rapidly when exposed to moisture. Such formulations typically do not have a long shelf life, in light of the difficulties inherent in excluding moisture during manufacture and storage.